DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Abstract

There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, highpenetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

Keywords: DNA repair; carcinogenesis; ovarian cancer; prognosis; therapy response.

Figure 1

DNA repair pathways and implications in cell biology. DNA damage in the G1/S checkpoint is repaired by non-homologous end-joining repair (NHEJ), base excision repair (BER) and nucleotide excision repair (NER). In the S phase checkpoint, DNA damage is repaired by mismatch repair (MMR), homologous recombination (HR), NHEJ, BER. G2/M checkpoint DNA damage repair pathways are NHEJ, BER, HR. [29,30,31,32].

Figure 2

Homologous recombination. Simplified scheme of homologous recombination in double-strand DNA breaks and DNA inter-strand crosslinks (gene alternations in OvC in bold, therapeutic interventions considered in OvC therapy marked by a red star (PARP inhibitors), purple star (check-point inhibitors)) [43]. Protein names: meiotic recombination 11 (MRE11), RAD50 homolog (RAD50), Nijmegen breakage syndrome 1 (NBS1), Ataxia telangiectasia mutated (ATM), replication protein A (RPA), Ataxia telangiectasia and RAD3 related-interacting protein (ATRIP), Ataxia telangiectasia and RAD3 related (ATR), checkpoint kinases (CHEK), retinoblastoma binding protein 8 (CtIP), breast cancer 1 and 2 (BRCA1 and 2), RAD51 homolog 1 (RAD51), BRCA1-interacting protein C-terminal helicase (BRIP1), partner and localizer of BRCA2 (PALB2) [44].

Figure 3

Non-homologous end-joining repair. Simplified scheme of non-homologous end-joining repair of double strand DNA breaks (gene alterations in OvC in bold) [32]. Protein names: DNA end-binding proteins Ku70/Ku80 (Ku70/Ku80), DNA-dependent protein kinase (DNA-PK), MRE11-RAD50-NBS1 complex (MRN complex), artemis (DCLRE1C), X-ray repair cross complementing-like factor. (XLF), X-ray repair cross complementing 4 (XRCC4), DNA ligase 4 (LIG4) [44].

Figure 4

Mismatch repair. Simplified scheme of mismatch repair of DNA mismatches or insertion/deletions mispairs (gene alternations in OvC in bold) [111]. Protein names: MutS homolog 2 (MSH2), MutS homolog 3 (MSH3), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), PMS1 homolog 1 (PMS1), PMS1 homolog 2 (PMS2), MutL homolog 3 (MLH3), replication protein A (RPA), exonuclease 1 (EXO1), replication factor C subunit 1 (RFC1), DNA polymerase delta (POLD), DNA ligase 1 (LIG1) [44].

Figure 5

Base excision repair. Simplified scheme of base excision repair of small base lesions (gene alternations in OvC in bold, therapeutic interventions considered in OvC therapy marked by red star (PARP inhibitors)) [128]. Protein names: single-strand selective monofunctional uracil DNA glycosylase (SMUG), uracil DNA glycosylase (UNG), 8-oxoguanine DNA glycosylase 1 (OGG1), endonuclease VIII-like (NEIL), MutY DNA glycosylase (MUTYH), apurinic/apyrimidinic endonuclease 1 and 2 (APE1 and 2), poly(ADP-ribose) polymerase 1 (PARP1), DNA polymerase beta, delta and epsilon (POLB, -D, -E), DNA ligase 1 and 3 (LIG1 and 3), X-ray repair cross-complementing 1 (XRCC1), replication factor C (RFC), Flap endonuclease 1 (FEN1), proliferating cell nuclear antigen (PCNA) [44].

Figure 6

Nucleotide excision repair. Simplified scheme of nucleotide excision repair of bulky lesions and helix distorting DNA damage DNA (gene alternations in OvC in bold, therapeutic interventions considered in OvC therapy marked by a red star (PARP inhibitors)) [150]. Protein names: damage specific DNA binding protein 2 (DDB2), xeroderma pigmentosum complementation group A, B, C, D, F, G (XPA, -B/ERCC3, -C, -D/ERCC2, -F/ERCC4, -G), Cockayne syndrome A and B (CSA and B), RNA polymerase II (RNA pol. II), excision repair cross-complementation group 1 (ERCC1), replication protein A (RPA), transcription factor II Human (TFIIH), poly(ADP-ribose) polymerase 1 (PARP1), proliferating cell nuclear antigen (PCNA), DNA polymerase delta and epsilon (POLD and E), DNA ligase 1 (LIG1) [44].

Figure 7

Direct repair. Simplified scheme of direct lesion reversal removing alkylation and UV-induced damage, and N-alkylated base adducts (gene alternations in OvC in bold) [162]. Protein names: O⁶-methylguanine DNA methyltransferase (MGMT), alpha-ketoglutarate-dependent dioxygenase AlkB (AlkB) [44].

Figure 8

Interplay of DNA repair pathways. Simplified scheme of interactions between proteins from distinct DNA repair pathways (genes interacting in OvC in bold). Gene names: breast cancer 1 and 2 (BRCA1 and 2), X-ray repair cross-complementing 1 (XRCC1), Ataxia telangiectasia mutated (ATM), xeroderma pigmentosum complementation group A and C (XPA and C), poly(ADP-ribose) polymerase 1 (PARP1). Protein inhibitors: apurinic/apyrimidinic endonuclease 1 inhibitors (APE1i), poly(ADP-ribose) polymerase inhibitors (PARPi).

Figure 9

The most important genes involved in DNA repair pathways in ovarian cancer. Scheme of DNA damage and the most important genes playing role in ovarian carcinogenesis, prognosis and therapy response NER (nucleotide excision repair), BER (base excision repair), NHEJ (non-homologous end-joining repair), MMR (mismatch repair), HR (homologous recombination), DR (direct repair)). Protein names: PMS1 homolog 2 (PMS2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), apurinic/apyrimidinic endonuclease 1 (APE1), poly(ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing 1 (XRCC1), MutY DNA glycosylase (MUTYH), 8-oxoguanine DNA glycosylase 1 (OGG1), breast cancer 1 and 2 (BRCA1 and 2), BRCA1-interacting protein C-terminal helicase (BRIP1), RAD50 homolog 1 (RAD50), RAD51 paralog C and paralog D (RAD51C and D), partner and localizer of BRCA2 (PALB2), alpha-ketoglutarate-dependent dioxygenase AlkB (AlkB), O⁶-methylguanine DNA methyltransferase (MGMT), DNA ligase 4 (LIG4), X-ray repair cross-complementing 4 (XRCC4), excision repair cross-complementation group 1 (ERCC1), xeroderma pigmentosum complementation protein C and D (XPC and D/ERCC2).